The invention relates to immunology, in particular to methods for influencing the immune system, and may be useful in therapy for diseases in mammals (humans and animals), including therapy for cancerous, autoimmune, and viral diseases.
A method for eliciting of an immune response to the formation of tumor cells in mammalian body disclosed in U.S. patent application No. 20030219420 comprises the following:
1) tumor treatment using a conventional method in order to eliminate the bulk of tumor cells in vivo (paragraph 0082 of said application);
2) treatment of a leukocyte concentrate, which is obtained by extracorporeal circulation of the blood of the tumor-bearing mammal, in a way that reduces the amount of blood plasma and serum proteins in the concentrate and, also, initiates the differentiation of monocytes, which, along with other cells, are present in the concentrate, into functional dendritic antigen-presenting cells (referred to hereinafter as APC), said treatment comprising pumping of the leukocyte concentrate through a system of plastic channels and filters; and
3) administering of the treated leukocyte concentrate back into the body.
It is expected that the antigenic structures of the tumor cells upon their interaction with dendritic cells will be presented by the latter, after their administration into the body, to T-cells thus eliciting the immune response of the body.
The basic disadvantage of said method is a high risk of tumor dissemination when it is insufficiently destroyed in vivo, e.g., by photodynamic therapy. Conventional treatments using chemotherapy or tumor irradiation or combinations thereof are known to invariantly compromise the entire immune system of the body. The resulting immunosuppression lasts long enough to make it unreasonable to expect that a significant stimulation of the immune system leading to an immune response will be achieved by administering of differentiated monocytes into the body, even upon the assumption that the monocytes differentiated in that way will have a sufficient functional activity in vivo, which needs sound experimental confirmations obtained in vivo.
Moreover, the author of said Application realizes himself that only a very small amount of the antigenic structures of the cells of a solid tumor may enter the circulatory system after tumor destruction (see paragraph 0053), and so the probability of their contact with the differentiated monocytes administered into the body is also very small. It has been suggested to increase the constant of binding of freely circulating antigenic structures to the treated monocytes administered into the body by additional administering of a certain amount of an antibody, which is specific to a certain type of tumor cells and easily binds to differentiated monocytes. However, it should be noted that, apart from the obvious meshing of treatment technology, the spectrum of antibodies that bind to a certain type of tumor cells is very limited and is far from encompassing all variants possible in the clinical practice.
Another known method for influencing the immune system of a mammal (U.S. Pat. No. 6,607,722; see also U.S. patent applications Nos. 20010053355, 20020098469, 20020114793, and 20020004044) comprises the following:
1) in vitro induction of APC formation from monocytes in a blood sample, which has been withdrawn from the body of the mammal, by a treatment using physical of chemical means;
2) subsequent co-incubation of the monocytes, which have differentiated into APC, with pathological biologically active elements, which have been obtained from the same mammal or are exogenous and which have undergone prior inactivation with physical influences or chemical means; and
3) administering of the mixture so obtained to said mammal.
Pathological biologically active elements (referred to hereinafter as PBE) are to be understood herein as any biological structures capable of causing a pathology and having at least one antigen associated therewith and being an individual immunological marker thereof. The examples of PBE include but are not limited to pathological cells capable of causing a disease (e.g., clones of immunocompetent cells in, e.g., autoimmune diseases), cells infected by a virus or affected by a microorganism, different microbes, viruses, and bacteria that circulate in a body, etc.
The use of the above method affords, according to data provided by its authors, a more prominent therapeutic effect vs. that afforded by the method according to prior art (U.S. Pat. No. 4,613,322), which has been named photopheresis.
At the same time, the method is laborious (see Examples in U.S. Pat. No. 6,607,722) and potentially less efficient than possible alternatives. The artificial in vitro differentiation of monocytes into APC after a prolonged physicochemical influence undermines the expectation that, upon administration of the so obtained APC into the body, their functional activity in vivo will be comparable to the functional activity of APC that have been formed by the natural cell differentiation in the body in the course of the development of an immune response to an antigenic stimulus. The required level of immunoreactivity of the administered immunocompetent cells is ensured by their sufficient amount and so is associated with a large volume of blood to be treated, which is quite traumatic to the patient undergoing such therapy.
The method for administration of the incubated mixture (intravenous, subcutaneous, intradermal, or intramuscular: see disclosure of U.S. Pat. No. 6,607,772) also does not provide for the optimal effect. It is known (see, e.g.: I. Roit, J. Brostoff, D. Male, Immunology, 1998, Mosby International, Ltd.) that the most important for foreign antigens presentation to resting T-cells are not tissue macrophages (including blood monocytes) but rather the so-called interdigital cells (referred to hereinafter as IDC) of the regional lymph nodes. APC located in the skin and other flat epithelium coatings of the body and, also, blood monocytes become transformed into IDC and capable of efficient antigen presentation to T-helpers for eliciting of the systemic immune response only after they have migrated via afferent lymphatics to the paracortical compartments of regional lymph nodes and have interacted with a series of T-cells there. As to the forced-differentiated blood monocytes administered into the body within the total cell mass, they can induce the generalized immune response only subsequent to the transfer of specific PBE markers bound thereto to the regional organs of the peripheral immune system.
Therefore, basing on the above, the method that appears to be the most similar to the method of the present invention is the method disclosed in U.S. Pat. No. 5,571,082 and implying the direct contact of processed antigens with IDC. According to said method, a leukocyte-enriched suspension obtained from a body liquid of a patient is exposed to optical radiation (within the visible of ultraviolet spectral regions) in the presence of a photochemical agent and then is returned back directly into the lymphatic system of the patient undergoing such treatment. When photo-adducts generated as a result of the covalent binding of the molecules of the photochemical agent to the components of pathological antigenic structures (e.g., antigenic structures of clones of pathological immunocompetent cells in lymphoproliferative malignant diseases or autoimmune conditions, of cells affected by viruses or bacteria, of viruses and bacteria circulating in the body, etc.) present in the fraction administered into the lymphatic system arrive in the body, their direct contact with IDC provides for the generalized immune response elicited in vivo without making damage to IDC and to the cells of the peripheral immune system. This does not require a special incubation of blood monocytes with the antigenic structures of pathological cells, viruses, or bacteria.
The main disadvantage of the above method is that the field of its application in the clinical practice is limited to pathological conditions (viral and bacterial infections, autoimmune conditions, and diseases of the blood and lymph systems, including blood and bone marrow malignancies) where the specific antigenic structures targeted by the immune response of the body are present directly in the biological fluids of a patient.